Amino acid and peptide absorption in patients with coeliac disease and dermatitis herpetiformis

A double-lumen perfusion technique has been used to study amino acid and peptide absorption in eight normal control subjects, 13 patients with untreated adult coeliac disease, and 16 patients with dermatitis herpetiformis who had varying morphological abnormalities of the small bowel. All subjects were perfused with isotonic solutions containing 10 mM glycyl-L-alanine and 10 mM glycine + 10 mM L-alanine.Patients with adult coeliac disease had impaired absorption of glycine (p < 0.01) and L-alanine (p < 0.05) from the amino acid solution compared with the control subjects. Amino acid uptake from the dipeptide solution was not significantly impaired, although four individual patients had impaired uptake of both amino acids. In contrast to these findings, very few patients with dermatitis herpetiformis had impaired amino acid absorption from either solution.Sodium absorption was impaired from both solutions when the groups of patients with adult coeliac disease and dermatitis herpetiformis with subtotal villous atrophy and partial villous atrophy were studied, and there were patients in each group who secreted sodium and water.The results suggest that malabsorption of dietary protein is unlikely to occur in dermatitis herpetiformis but may occur and contribute to protein deficiency seen in some severe cases of adult coeliac disease. The impairment of sodium and water absorption provides evidence that there may be functional impairment of the jejunal mucosa in dermatitis herpetiformis as well as in adult coeliac disease.     

Wheat starch-containing gluten-free flour products in the treatment of coeliac disease and dermatitis herpetiformis. A long-term follow-up study

BACKGROUND: We investigated whether wheat starch-based gluten-free products are safe in the treatment of gluten intolerance. METHODS: The study involved 41 children and adults with coeliac disease and 11 adults with dermatitis herpetiformis adhering to a gluten-free diet for 8 years on average. Thirty-five newly diagnosed coeliac patients at diagnosis and 6 to 24 months after the start of a gluten-free diet and 27 non-coeliac patients with dyspepsia were investigated for comparison. Daily dietary gluten and wheat starch intake were calculated. Small-bowel mucosal villous architecture, CD3+, alphabeta+, and gammadelta+ intraepithelial lymphocytes, mucosal HLA-DR expression, and serum endomysial, reticulin, and gliadin antibodies were investigated. RESULTS: Forty of 52 long-term-treated patients adhered to a strict wheat starch-based diet and 6 to a strict naturally gluten-free diet; 6 patients had dietary lapses. In the 46 patients on a strict diet the villous architecture, enterocyte height, and density of alphabeta+ intraepithelial lymphocytes were similar to those in non-coeliac subjects and better than in short-term-treated coeliac patients. The density of gammadelta(+)cells was higher, but they seemed to decrease over time with the gluten-free diet. Wheat starch-based gluten-free flour products did not cause aberrant upregulation of mucosal HLA-DR. The mucosal integrity was not dependent on the daily intake of wheat starch in all patients on a strict diet, whereas two of the six patients with dietary lapses had villous atrophy and positive serology. CONCLUSION: Wheat starch-based gluten-free flour products were not harmful in the treatment of coeliac disease and dermatitis herpetiformis.     

Jejunal mucosal immunoglobulin-containing cells and jejunal fluid immunoglobulins in adult coeliac disease and dermatitis herpetiformis

Immunoglobulin-containing plasma cell densities in the jejunal mucosa and serum and jejunal fluid immunoglobulins have been measured in patients with adult coeliac disease and dermatitis herpetiformis with and without jejunal mucosal abnormality. Studies were performed in patients before and after treatment of the jejunal lesion.

Total immunofluorescent plasma cells were increased in untreated adult coeliac disease and dermatitis herpetiformis patients with jejunal lesions, but in general the normal predominance of IgA > IgM > IgG was found. There was no difference from controls in IgA-containing cells in the two conditions before or after treatment. The numbers of IgM-containing cells were significantly increased both before and after treatment in groups of patients with adult coeliac disease and dermatitis herpetiformis who had jejunal lesions. IgG-containing cells were significantly raised in only the before-treatment groups. Patients with dermatitis herpetiformis without jejunal lesions, even whilst on gluten-containing diets, had normal numbers of immunoglobulin-containing cells. IgA and IgM jejunal fluid immunoglobulins were significantly raised in dermatitis herpetiformis and adult coeliac disease.

It is concluded that patients with dermatitis herpetiformis with jejunal morphological abnormality have a comparable immunological disturbance of the jejunal mucosa to that found in adult coeliac disease.

     

Dermatitis herpetiformis: diagnosis, diet and demography

We describe a long term study of 76 patients with dermatitis herpetiformis. Unlike patients with coeliac disease, where the peak incidence was during the first and fourth decades, no dermatitis herpetiformis patients presented in the first decade; also, there was a male preponderance in dermatitis herpetiformis which contrasts with the excess of females in coeliac disease. The apparent prevalence of dermatitis herpetiformis was 11 per 100 000 in our population; approximately one fifth of that of coeliac disease. Jejunal villous atrophy was present in 78% of our dermatitis herpetiformis patients, and a single jejunal biopsy was as effective at detecting this as the multiple biopsy technique. A majority of patients were able to stop, or radically reduce their dapsone or sulphapyridine treatment after the institution of a gluten free diet. Spontaneous remission of the skin lesion occurred in only two patients not receiving a gluten free diet. Gastric parietal or thyroid antibodies were detected in 38% of patients, and three cases of thyroid disease and two cases of pernicious anaemia were detected. Lymphoma developed in two patients, one being intestinal in origin. We conclude that a gluten free diet is of therapeutic benefit in dermatitis herpetiformis and that spontaneous remission is uncommon in those not on a diet. Despite patchiness of the enteropathy, a single jejunal biopsy is quite adequate to diagnose the presence of upper intestinal villous atrophy.     

Gastric morphology and function in dermatitis herpetiformis and in coeliac disease

Gastric acid secretory capacity was evaluated in 116 patients with dermatitis herpetiformis by means of the pentagastrin test. Endoscopic gastric mucosal biopsy specimens were obtained from both the body and the antrum in 90 of them. Forty-eight patients (41%) had a maximal acid output less than 10 mmol/h, and 30 of them (26%) were achlorhydric. The frequency of achlorhydria increased with age, and 27 out of 58 patients (47%) more than 50 years old were achlorhydric. Antrum-sparing chronic atrophic gastritis was present in 92% of the achlorhydric patients, and hypergastrinaemia and serum parietal cell antibodies were found in most of them. The prevalence of chronic gastritis of the body and of the antrum increased with age. There was no correlation between atrophic gastritis or achlorhydria and small-intestinal villous atrophy, the results of the D-xylose test, and blood folate and serum zinc determinations. The transferrin saturation index was lower in patients with achlorhydria. The frequency of achlorhydria was significantly higher in patients with dermatitis herpetiformis than in 69 patients with coeliac disease.     

Relevance of the barium follow-through examination in the diagnosis of adult celiac disease

Significant changes on a standard barium follow-through examination in celiac disease have been determined by comparison with functional changes (irritable bowel syndrome), malabsorption without a villous lesion (chronic pancreatitis), and a villous abnormality without malabsorption (dermatitis herpetiformis). Patients with iron deficiency anemia formed the control group. Slight jejunal dilatation (26-30 mm) was found in 15% of the celiacs and 17% of the irritable bowel patients. Dilatation in excess of 30 mm and/or effacement of jejunal fold pattern occurred only with an abnormal jejunal biopsy, in 54% of the celiacs and 33% of the dermatitis herpetiformis patients. Patients with malabsorption by itself and 46% of the celiacs could not be distinguished from those with irritable bowel syndrome. The concept of a malabsorption pattern is considered invalid, and the diagnosis of celiac disease can be reliably established only by peroral jejunal biopsy.     

Serum antibodies to gliadin and small-intestinal morphology in dermatitis herpetiformis. A controlled clinical study of the effect of treatment with a gluten-free diet

Serum gliadin antibodies of the IgA and IgG classes were determined by the diffusion-in-gel enzyme-linked immunosorbent assay in 41 patients with dermatitis herpetiformis before treatment with a gluten-free diet. Increased gliadin antibody levels were found more frequently in patients with subtotal villous atrophy (9 out of 17 patients, or 53%; p less than 0.05) than in patients with partial villous atrophy (2 out of 13 patients, or 15%) or normal villous appearance (2 out of 10 patients, or 20%). The gliadin antibody levels were negatively correlated with the urinary xylose excretion (r = -0.40, p less than 0.02 for the IgA class and r = -0.64, p less than 0.001 for the IgG class). Intestinal morphology improved and mean gliadin antibody levels of the IgA and IgG classes decreased during treatment with a gluten-free diet for 16-36 months (mean, 20 months) (p less than 0.005, n = 26), whereas no significant changes of the gliadin antibody levels or the small-intestinal morphology were observed in the other 15 patients, who continued on a non-restricted diet for 17-35 months (mean, 20 months). Thus, gliadin antibody levels in sera from patients with dermatitis herpetiformis seem to be correlated with the severity of the intestinal disease. However, all patients with villous atrophy are not detected by determination of serum gliadin antibodies.     

Bone Mass and Metabolism in Dermatitis Herpetiformis

Dermatitis herpetiformis is a gluten-sensitiveskin disease with intestinal lesions and malabsorptionsymptoms less severe than those found in celiac disease.While several studies have shown the occurrence of osteopenia in celiac disease, bone mass andmetabolism have never before been evaluated indermatitis herpetiformis. Therefore, in 16 untreatedpatients, 16 sex- and age-matched untreated celiacpatients, and 16 sex- and age-matched healthy volunteers,lumbar and femoral bone mineral density were measuredand bone and mineral metabolism and nutritional statuswere evaluated. All these parameters were significantly altered in the two groups of patients andalthough the degree of these alterations was milder inpatients with dermatitis herpetiformis than in celiacpatients, the presence of subtotal villous atrophy in patients with dermatitis herpetiformis wasassociated with the presence of more severe alterations.Bone mineral density was significantly correlated withnutritional status, and patients showing bone loss were characterized by a body mass indexlower than 20. Alterations of bone mass and mineralmetabolism complicate dermatitis herpetiformis whensevere intestinal lesions coexist. A low nutritional status may be predictive of the presence ofbone loss.     

T-cell and plasma cell populations in coeliac small intestinal mucosa in relation to dermatitis herpetiformis.

Differential lymphocyte and plasma cell counts and measurements of mucosal architecture were studied in small intestinal biopsies from 17 controls and 17 patients with untreated uncomplicated coeliac disease of whom five also had dermatitis herpetiformis. Intraepithelial T-cell and plasma cell counts and measurements of mucosal architecture were not significantly different in the two coeliac groups but both groups differed from the controls. Lamina propria T-cell counts were significantly higher in the patients who also had dermatitis herpetiformis than in uncomplicated coeliac disease, with a significant increase in the Leu 2 (CD8) positive (cytotoxic/suppressor) T-cell subset. This suggests a specific abnormality of T-cell control of immune responsiveness in the pathogenesis of the skin manifestations of dermatitis herpetiformis which is not found in uncomplicated coeliac disease.     

Patchiness and duodenal-jejunal variation of the mucosal abnormality in coeliac disease and dermatitis herpetiformis.

The incidence and degree of patchiness of mucosal abnormality in both coeliac disease (CD) and dermatitis herpetiformis (DH) is documented. As judged by both stereomicroscopy and subjective histology, patchiness occurred frequently in both CDand DH patients. In most cases the difference of abnormality was of only one grade, but in approximately 25% as assessed by stereomicroscopy and 10% as assessed by histology the difference was of two or more grades. In control subjects with normal small bowel mucosa the variation of the mucosal appearance between the duodenum and proximal jejunum was studied. Contrary to popular belief, no significant difference of villous and crypt measurements or of apparent villous "bridging" and "branching" between these two sites was found, if only well-orientated sections were studied. The stereomicroscopic appearances were also similar at these two sites, although villi tended to be broader in the duodenal biopsies. The duodenal-jejunal variation was also studied in CD and DH patients and although by both stereomicroscopy and subjective histology the appearances were similar in most patients, in approximately 33% the duodenal abnormality was the most severe and, surprisingly, the jejunal abnormality was more severe in approximately 15%. It is concluded that multiple, precisely located biopsies of both the duodenum and proximal jejunum are invaluable in the investigation of small bowel disease and in assessing response to treatment.     

HLA association with dermatitis herpetiformis is accounted for by a cis or transassociated DQ heterodimer.

HLA-DR, DQ, and DP restriction fragment genotyping was undertaken in 23 dermatitis herpetiformis patients and 53 healthy control subjects. HLA-DQw2 was present in 100% of patients with dermatitis herpetiformis (23 of 23) versus 40% of control subjects (21 of 53). Significant secondary associations occurred with HLA-DR3 (91% of patients versus 28% of control subjects) and DPw1 (39% of patients versus 11% of control subjects). Dermatitis herpetiformis and coeliac disease thus share an identical HLA class II association. It is likely that HLA class II genes directly influence the immune responses leading to mucosal damage in both diseases. The strongest candidate for disease susceptibility to dermatitis herpetiformis is DQw2. The HLA molecule most likely to be involved in coeliac disease is a specific DQ alpha/DQ beta heterodimer, encoded in cis arrangement in DR3 haplotypes or in trans arrangement in a DR5, 7 genotype. Our data on dermatitis herpetiformis patients fits this model perfectly. All these patients are capable of expressing this molecule, which may be responsible for the gluten sensitive enteropathy seen in a subgroup of patients with dermatitis herpetiformis and coeliac disease.     

Association of subepithelial deposition of activated complement and immunoglobulin G and M response to gluten in celiac disease.

Patients with celiac disease produce not only immunoglobulin A (IgA) but also immunoglobulin G (IgG) and M (IgM) antibodies to gluten. Intake of dietary gluten may hence induce local complement activation and mucosal damage. Jejunal tissue sections from adult patients with celiac disease were examined by immunofluorescence with monoclonal antibodies to activation neoepitopes in C3b and the terminal complement complex (TCC). Subepithelial deposition of TCC was observed in 93% of 28 untreated and in 57% of 23 partly treated study subjects. The immunofluorescence staining intensity was well correlated with the serum level of gluten-specific IgG and IgM (but not IgA), the number of mucosal IgG-producing cells, and the degree of villous atrophy. Similar immune deposits were not observed in 5 successfully treated patients with celiac disease, 5 patients with dermatitis herpetiformis without jejunal villous atrophy, and 90% of 21 control patients with histologically normal jejunal mucosa. Gluten challenge increased the amount of subepithelial TCC and produced additional C3b deposition, suggesting recent complement activation. Ingested gluten might thus, via Ig-mediated subepithelial complement activation, damage the surface epithelium in celiac disease and induce compensatory crypt hyperplasia.     

Malignancy and survival in dermatitis herpetiformis: a comparison with coeliac disease.

BACKGROUND--Dermatitis herpetiformis is a lifelong, gluten sensitive skin disease. Patients with dermatitis herpetiformis, similar to patients with coeliac disease not adhering to a gluten free diet, seem to have increased risk for lymphoma. AIMS--This study looked at the occurrence of malignancy and survival of patients with dermatitis herpetiformis and compared the results with those seen in patients with coeliac disease or in the general population. PATIENTS--A total of 305 adult patients with dermatitis herpetiformis diagnosed at the University Hospital of Tampere in 1970-1992 were studied. Most patients started a gluten free diet and at the end of the study 93% of the patients were adhering to the diet. A control group comprised 383 adult patients with coeliac disease, 81% of them adhered to a gluten free diet, 6% had a normal diet, and in 13% the diet history remained unknown. METHODS--The occurrence of malignant diseases and survival of the patients were assessed up to the end of 1993. Standardised incidence ratios (SIR) with 95% confidence intervals were used for the malignant diseases. The survival of the patients was compared with that of the general population. RESULTS--Thirteen (4.3%) patients with dermatitis herpetiformis developed 14 malignant disorders during the follow up (SIR 1.25; 95% confidence intervals 0.68 to 2.09). A non-Hodgkin's lymphoma occurred in four patients with dermatitis herpetiformis, significantly more than expected (SIR 10.3; 2.8-26.3). Thirteen (4.3%) patients with dermatitis herpetiformis died during the follow up but there was no increased general mortality. In coeliac disease, 13 (3.4%) patients developed malignancy (SIR 1.16; 0.62 to 1.97), 31 (8.1%) patients died but the survival rate did not differ from that in the general population. CONCLUSIONS--The incidence of non-Hodgkin's lymphoma was significantly increased in patients with dermatitis herpetiformis. The results also confirm that the patients with dermatitis herpetiformis treated mainly with a gluten free diet have no increased general mortality.     

In vivo targeting of intestinal and extraintestinal transglutaminase 2 by coeliac autoantibodies

BACKGROUND: IgA class serum autoantibodies against type 2 (tissue) transglutaminase (TG2) bind to both intestinal and extraintestinal normal tissue sections in vitro, eliciting endomysial, reticulin, and jejunal antibody reactions. It is not known whether similar binding also occurs in coeliac patients in vivo, and may thereby contribute to disease manifestations. AIMS: To investigate intestinal and extraintestinal coeliac tissues for the presence of in vivo bound TG2 specific IgA and its relation to small intestinal mucosal atrophy. PATIENTS: We investigated jejunal samples with normal villous morphology from 10 patients with developing coeliac disease who subsequently progressed to a flat lesion, from 11 patients with dermatitis herpetiformis, and from 12 non-coeliac controls. Six extrajejunal biopsy samples (liver, lymph node, muscle, appendix), obtained based on independent clinical indications from patients with active coeliac disease, were also studied. METHODS: Double colour immunofluorescent studies for in situ IgA, TG2, and laminin were performed. IgA was eluted from tissue sections and tested for TG2 specificity by enzyme linked immunosorbent assay and indirect immunofluorescence. RESULTS: IgA (in one IgA deficient case IgG) deposition on extracellularly located TG2 was detected in jejunal and extrajejunal specimens of all coeliac patients, and also in seven of 11 dermatitis herpetiformis patients, of whom two had no circulating endomysial antibodies. IgA eluted from extraintestinal coeliac tissues was targeted against TG2. CONCLUSIONS: Coeliac IgA targets jejunal TG2 early in disease development even when endomysial antibodies are not present in the circulation. Extraintestinal target sites of coeliac IgA further indicate that humoral immunity may have a pathogenetic role.     

Small intestinal mucosal abnormalities in relatives of patients with dermatitis herpetiformis

Jejunal biopsy has been carried out in 19 relatives of patients with dermatitis herpetiformis and stereomicroscopic abnormalities have been found in seven. The majority of the relatives in whom these abnormalities were found had no bowel symptoms: one had the rash of dermatitis herpetiformis. All but one of the propositi of the relatives in whom were found small intestinal mucosal abnormalities themselves had the coeliac syndrome. It is concluded that a genetic factor is involved in the production of the enteropathy of dermatitis herpetiformis as in other forms of the coeliac syndrome.     

First-degree relatives are frequently affected in coeliac disease and dermatitis herpetiformis

BACKGROUND: Coeliac disease and dermatitis herpetiformis are phenotypically distinct gluten-sensitive diseases. Coeliac disease is known to cluster in families, whereas there is little evidence for dermatitis herpetiformis and for the occurrence of both diseases in the same families. METHODS: The study group comprised 380 patients with coeliac disease and 281 patients with dermatitis herpetiformis, with a total of 3158 first-degree relatives, followed up for a mean of 14 years. The patients were questioned about affected first-degree relatives. The prevalence and incidence of biopsy-proven coeliac disease and dermatitis herpetiformis in relatives were determined. RESULTS: Seventy-three (19.2%) patients with coeliac disease and 51 (18.1%) with dermatitis herpetiformis had affected first-degree relatives. The prevalence among relatives was similar for both diseases; 4.7% and 3.9% of the relatives had coeliac disease and 0.8% and 1.5% had dermatitis herpetiformis, respectively. The disease prevalence was 7% among siblings, 4.5% among parents and 3.5% among children. The annual incidence was 3/1,000 relatives, which is 15 times higher than among the general population. Coeliac disease and dermatitis herpetiformis were mixed in several multiple-case families. CONCLUSIONS: The present long-term follow-up study of coeliac disease and dermatitis herpetiformis shows that every fifth patient can have affected first-degree relatives, and that the prevalence among relatives is 5.5%. Dermatitis herpetiformis segregates also in the families of patients with coeliac disease, and vice versa, indicating the same genetic background.     

First-degree Relatives Are Frequently Affected in Coeliac Disease and Dermatitis Herpetiformis

Background: Coeliac disease and dermatitis herpetiformis are phenotypically distinct gluten-sensitive diseases. Coeliac disease is known to cluster in families, whereas there is little evidence for dermatitis herpetiformis and for the occurrence of both diseases in the same families. Methods: The study group comprised 380 patients with coeliac disease and 281 patients with dermatitis herpetiformis, with a total of 3158 first-degree relatives, followed up for a mean of 14 years. The patients were questioned about affected first-degree relatives. The prevalence and incidence of biopsy-proven coeliac disease and dermatitis herpetiformis in relatives were determined. Results: Seventy-three (19.2%) patients with coeliac disease and 51 (18.1%) with dermatitis herpetiformis had affected first-degree relatives. The prevalence among relatives was similar for both diseases; 4.7% and 3.9% of the relatives had coeliac disease and 0.8% and 1.5% had dermatitis herpetiformis, respectively. The disease prevalence was 7% among siblings, 4.5% among parents and 3.5% among children. The annual incidence was 3/1000 relatives, which is 15 times higher than among the general population. Coeliac disease and dermatitis herpetiformis were mixed in several multiple-case families. Conclusions: The present long-term follow-up study of coeliac disease and dermatitis herpetiformis shows that every fifth patient can have affected first-degree relatives, and that the prevalence among relatives is 5.5%. Dermatitis herpetiformis segregates also in the families of patients with coeliac disease, and vice versa, indicating the same genetic background.     

Monozygous twins concordant for duodenojejunal villous atrophy and dermatitis herpetiformis.

A pair of monozygous twins concordant for both duodenojejunal villous atrophy and dermatitis herpetiformis are described, the first example to be reported in the literature. The observation provides strong support for the concept of an underlying genetic component being involved in the pathogenesis of these two conditions.     

Gastric Secretion of Acid and Intrinsic Factor in Dermatitis Herpetiformis

Gastric acid and intrinsic factor secretion studies before and after penta-gastrin stimulation have been performed in 10 patients with dermatitis herpetiformis. Three patients had achlorhydria, and 6 had low gastric acid secretion. All but one had low secretion of intrinsic factor. Two patients had serum antibodies against gastric parietal cells. There was no correlation between the gastric abnormality and the patient's age, the intensity of the skin disease, the sulphone medication, or small-bowel mucosal structure. The only patient with normal gastric secretion also had the shortest duration of the skin disease. The ‘gastropathy’ in dermatitis herpetiformis further strengthens the similarity of its enteropathy to coeliac disease.     

Tolerance to oats in dermatitis herpetiformis

Objectives—Recent studies on coeliac diseasehave shown that oats can be included in a gluten-free diet withoutadverse effects on the small bowel. The presence of a rash is also asensitive indicator of gluten ingestion in dermatitis herpetiformis,and this was used to study whether patients with this disease could also tolerate oats.
Patients/Methods—Eleven patients with dermatitisherpetiformis in remission on a gluten-free diet were challenged dailywith 50 g oats for six months. Clinical symptoms were recorded, serum samples taken, and skin and small bowel biopsies performed before andafter the oat challenge. A control group comprised of 11 patients withdermatitis herpetiformis on a conventional gluten-free diet was also studied.
Results—Eight patients challenged with oatsremained asymptomatic, two developed a transient rash, and one withdrewbecause of the appearance of a more persistent but mild rash. Three of the 11 controls also developed a transient rash. IgA endomysial antibodies remained negative in all patients. The small bowel villous architecture, the densities of intraepithelial CD3 and α/βand γ/δ T cell receptor positive lymphocytes and crypt epithelial cell DR expression remained unaltered during the oat challenge.
Conclusions—The results confirm the absenceof oat toxicity on the gluten sensitive small bowel mucosa and suggestthat the rash in patients with dermatitis herpetiformis is notactivated by eating oats.

Keywords:dermatitis herpetiformis; coeliac disease; gluten-free diet; oats